This invention relates to a process for producing substituted pyrroles, especially pyrrole-2-acetic acids and derivative compounds thereof. More particularly, the process of this invention is concerned with processes which produce 1,4-diloweralkyl-3-loweralkoxycarbonyl-pyrrole-2-acetate which is a useful intermediate for analgesic and anti-inflammatory pharmaceutical compounds.
It has been found difficult in the past to substitute pyrrole rings, which already contain substituents at other positions on the ring, at the 4-position because of steric hindrance and ring deactivation. Thus, Carson, U.S. Pat. Nos. 3,752,826 and 3,865,840, teach the preparation of certain 4-substituted 5-aroyl-pyrrole alkanoic acids and the corresponding salts, esters, nitriles, amides and substituted amides thereof represented by the formulas: ##STR1## wherein: Ar represents a member selected from the group consisting of phenyl, monosubstituted phenyl and polysubstituted phenyl, each substituent of said substituted phenyls being a member selected from the group consisting of halo, lower alkyl and lower alkoxy;
Ar.sub.1 represents a member selected from the group consisting of phenyl, thienyl, 5-methylthienyl, monosubstituted phenyl and polysubstituted phenyl, each substituent of said substituted phenyls being a member selected from the group consisting of halo, lower alkyl, trifluoromethyl, lower alkoxy, nitro, amino, cyano, and methylthio; PA0 R represents a member selected from the group consisting of COOH, COO-(lower alkyl), CONH.sub.2, CONH-(lower alkyl) and CON-(lower alkyl).sub.2 ; PA0 R.sub.1 represents lower alkyl; PA0 R.sub.2 represents a member selected from the group consisting of hydrogen and lower alkyl, provided that when said Ar is a member of the group consisting of nitrosubstituted phenyl, then, with regard to Formula III, R.sub.2 is hydrogen; PA0 Me is methyl;
and the non-toxic, therapeutically acceptable salts of such acids, such as are obtained from the appropriate organic and inorganic bases. According to Carson, supra, the 4-substituted 5-aroyl-pyrrole alkanoic acids must be obtained by condensation of the appropriate 1-aryl-1,2,3,-butanetrione-2-oxime and an appropriate dialkyl acetonedicarboxylate as starting materials to provide the corresponding ring closed pyrrole, alkyl 5-aroyl-3-alkoxycarbonyl-4-methylpyrrole-2-acetate; or by condensation of an appropriate chloromethyl lower alkyl ketone added to a mixture of an appropriate di-loweralkyl acetonedicarboxylate, preferably the diethyl ester and a lower alkyl amine to provide the ring-closed pyrrole, alkyl 1,4-diloweralkyl-3-alkoxycarbonyl pyrrole-2-acetate. These pyrrole intermediates are then treated as disclosed in U.S. Pat. Nos. 3,752,826 and 3,865,840 to obtain the desired 5-aroyl-4-lower alkyl-pyrrole-2-alkanoic acids and acid derivatives thereof useful as anti-inflammatory agents.
The condensation of chloromethylketone, ammonia and hydroxy crotonic acid alkylester through an anticrotonic acid ester is taught by Fischer and Orth, Die Chemie Des Pyrroles, pp. 5-6, and 233-234, Edward Brothers, Inc., Ann Arbor, Mich., 1943. However, neither the 4-alkyl-substituent nor the diester functionality are disclosed in this reference.
Another pyrrole ring-closure synthesis, known as the Hantzsch pyrrole synthesis, teaches the interaction of alphachloro-aldehydes or ketones with beta-ketoesters and ammonia or amines to give pyrroles, Gowan and Wheeler, Name Index of Organic Reactions, p. 116. Longmans, Green and Co., Ltd., New York, N.Y., 1960.
In a similar manner, there is taught the reaction of chloroacetone with a salt produced from reaction of methylamine and diethyl acetone dicarboxylate to give a 4-methylpyrrole, Jones and Bean, The Chemistry of Pyrroles, pp. 59, 104, Academic Press, Inc., New York, 1977. Also, the pyrrole synthesis from chloromethyl ketones and beta-ketocarboxylic esters with ammonia or amines is known, Krauch and Kunz, Organic Name Reactions, p. 211, John Wiley and Sons, Inc., New York, 1964. However, such teachings either fail to suggest the possibility of the pyrrole diester compounds or teach no more than Carson, supra, and are based thereon.
Specifically pertinent to the improved process of this invention, U.S. Pat. Nos. 3,752,826 and 3,865,840 teach that after reaction of, for example, aqueous methylamine with diethyl acetone dicarboxylate and then adding chloroacetone at a temperature just below 60.degree. C. for a period of two hours, the resultant reaction mixture is poured into ice-hydrochloric acid. The acidification acts to dehydrate the intermediate dihydroxy pyrrolidine to the desired pyrrole. However, the reaction forms solid intermediates which are difficult to agitate and conversion of the intermediates to the desired product results in an exothermic reaction which is difficult to control on a large scale. In an attempt to overcome the solids formation problem, the reaction of diethyl acetone dicarboxylate with chloroacetone and aqueous methylamine was carried out in the presence of an added co-solvent, e.g., a halogenated hydrocarbon, such as methylene chloride, or an aromatic hydrocarbyl compound, such as toluene, at temperatures from 25.degree. C. to 40.degree. C. by Messrs. Dagani and Kao, respectively, as described in patent applications Ser. Nos. 137,231 and 137,250 now pending, both filed on Apr. 4, 1980. Further, it was discovered by Messrs. Kao and Farritor that when conducting the reaction at even lower temperatures, say from 0.degree. C. to about 15.degree. C., that even in the presence of an added co-solvent, such as methylene chloride, solids formation with its attendant lower contacting and mixing problems could occur. It was, however, discovered by Messrs. Kao and Farritor that the addition to the reaction mixture of a lower alkanol having from 1 to about 6 carbon atoms served to aid the dissolution of solids formed in the reaction mixture at temperatures down to about 0.degree. C. as described in patent application Ser. No. 239,431 filed on Mar. 2, 1981.
In U.K. patent application No. GB 2,034,304 A there is disclosed a process for producing a substituted pyrrole of the formula: ##STR2## wherein R.sub.1 is a hydrocarbyl group of up to about 20 carbon atoms, R.sub.2 and R.sub.3 are independently alkyl or aralkyl of up to about 20 carbon atoms and R.sub.4 is H or a hydrocarbyl of up to about 20 carbon atoms which comprises reacting a primary amine R.sub.1 NH.sub.2 with an acetone dicarboxylic acid diester: EQU R.sub.3 OOCCH.sub.2 COCH.sub.2 COR.sub.2
and a substituted carbonyl compound R.sub.4 COCH.sub.2 X where X is a leaving group. The pyrrole forming reaction is conducted in a two-phase aqueous/organic reaction medium dispersion containing R.sub.1 NH.sub.2 with which the acetone dicarboxylic acid ester and substituted carbonyl compound are combined and/or in a reaction medium containing R.sub.1 NH.sub.2 to which the acetone dicarboxylic acid ester and substituted carbonyl compounds are added in a substantially simultaneous manner.
In patent application Ser. No. 137,511, now pending, filed Apr. 4, 1981, there is described a method for obtaining the desired loweralkyl 1,4-diloweralkyl-3-loweralkoxycarbonyl-pyrrole-2-acetate by adding chloromethylloweralkyl ketone to a pre-mixed cooled solution of aqueous loweralkylamine and a diloweralkyl acetone dicarboxylate in a suitable solvent with reaction at below 60.degree. C., and heating the resultant reaction mixture to from about 70.degree. C. to 100.degree. C. for a period of time sufficient to dehydrate the dihydroxy pyrrolidine intermediate in the resultant reaction mixture and produce the desired loweralkyl 1,4-diloweralkyl-3-loweralkoxycarbonyl-pyrrole-2-acetate.